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Current Status and Future Direction of Immunotherapy in Urothelial Carcinoma

  • Genitourinary Cancers (DP Petrylak and JW Kim, Section Editors)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Since 2016, five new programmed cell death protein 1/ligand 1 (PD-1/L1) checkpoint inhibitors have been approved for metastatic urothelial carcinoma. This review will summarize the data supporting the widespread use of these agents and highlight areas of ongoing clinical development.

Recent Findings

PD-1/L1 axis inhibition has demonstrated clear superiority to chemotherapy for the treatment of metastatic urothelial cancer in the second-line setting. A multitude of ongoing studies are investigating the feasibility and efficacy of incorporating established and novel immunotherapies into earlier lines of therapy, including non-metastatic muscle-invasive bladder cancer and even non-muscle-invasive disease. Early-phase clinical trials have begun to explore the safety and activity of novel immune-oncology combinations across a range of clinical settings.

Summary

Immunotherapy has a clearly defined role in the treatment of metastatic urothelial cancer both in the platinum-refractory setting and in the first-line cisplatin-ineligible setting. Ongoing clinical trials will dictate how to best incorporate immunotherapy into earlier lines of therapy and define the safety and activity of novel immunotherapy agents and combinations.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.

    Article  Google Scholar 

  2. Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer. 2015;15(1):25–41.

    Article  CAS  Google Scholar 

  3. Roupret M, Babjuk M, Comperat E, Zigeuner R, Sylvester RJ, Burger M, et al. European Association of Urology guidelines on upper urinary tract urothelial cell carcinoma: 2015 update. Eur Urol. 2015;68(5):868–79.

    Article  Google Scholar 

  4. Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent Ta, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group study. J Urol. 2000;163(4):1124–9.

    Article  CAS  Google Scholar 

  5. Skinner DG, Lieskovsky G. Contemporary cystectomy with pelvic node dissection compared to preoperative radiation-therapy plus cystectomy in management of invasive bladder cancer. J Urol. 1984;131(6):1069–72.

    Article  CAS  Google Scholar 

  6. Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859–66.

    Article  CAS  Google Scholar 

  7. Sternberg CN, Skoneczna I, Kerst JM, Albers P, Fossa SD, Agerbaek M, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 2015;16(1):76–86.

    Article  Google Scholar 

  8. von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, et al. Long-term-survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23(21):4602–8.

    Article  Google Scholar 

  9. Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558−+.

    Article  Google Scholar 

  10. Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J Clin Oncol. 2012;30(10):1107–13.

    Article  CAS  Google Scholar 

  11. Bellmunt J, Theodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009;27(27):4454–61.

    Article  CAS  Google Scholar 

  12. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7.

    Article  CAS  Google Scholar 

  13. •• Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–20 Registrational phase 2 study of atezolizumab in platinum-refractory mUC.

    Article  CAS  Google Scholar 

  14. • Powles T, Duran I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391(10122):748–57 Negative phase 3 study of atezolizumab in platinum-refractory mUC.

    Article  CAS  Google Scholar 

  15. Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, et al. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012;30(5):507–12.

    Article  CAS  Google Scholar 

  16. Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002;20(4):937–40.

    Article  CAS  Google Scholar 

  17. Balar A, Bellmunt J, O’Donnell PH, Castellano D, Grivas P, Vuky J, et al. Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: Preliminary results from the phase 2 KEYNOTE-052 study. Ann Oncol. 2016;27(suppl_6).

  18. Plimack ER, Bellmunt J, Gupta S, Berger R, Chow LQ, Juco J, et al. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. Lancet Oncol. 2017;18(2):212–20.

    Article  CAS  Google Scholar 

  19. •• Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26 Positive phase 3 trial of pembrolizumab in platinum-refractory mUC.

    Article  CAS  Google Scholar 

  20. •• Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312–22 Registrational phase 2 study of nivolumab in platinum-refractory mUC.

    Article  CAS  Google Scholar 

  21. Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, et al. Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol. 2016;34(26):3119–25.

    Article  CAS  Google Scholar 

  22. •• Powles T, O’Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(9):e172411 Registrational phase 2 study of durvalumab in platinum refractory mUC.

    Article  Google Scholar 

  23. Marlon Rebelatto AM, Sabalos C, Walker J, Midha A, Steele K, Robbins PB, et al. Development of a PD-L1 companion diagnostic assay for treatment with MEDI4736 in NSCLC and SCCHN patients. J Clin Oncol. 2015;33(suppl; abstr 8033).

  24. •• Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M, Aljumaily R, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018;19(1):51–64 Registrational phase 2 study of avelumab in platinum-refractory mUC.

    Article  CAS  Google Scholar 

  25. Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992;10(7):1066–73.

    Article  Google Scholar 

  26. Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, et al. Treatment of patients with metastatic urothelial cancer “unfit” for cisplatin-based chemotherapy. J Clin Oncol. 2011;29(17):2432–8.

    Article  Google Scholar 

  27. De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012;30(2):191–9.

    Article  Google Scholar 

  28. •• Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67–76 Registrational phase 2 study of atezolizumab in first-line cisplatin-ineligible muC.

    Article  CAS  Google Scholar 

  29. •• Balar AV, Castellano D, O’Donnell PH, Grivas P, Vuky J, Powles T, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483–92 Registrational phase 2 study of pembrolizumab in first-line cisplatin-ineligible muC.

    Article  CAS  Google Scholar 

  30. Vida AR, Mellado B, del Muro XG, Taus A, Barrera RM, Maroto P. Phase II randomized study of first line avelumab with carboplatin-gemcitabine versus carboplatin-gemcitabine alone in patients with metastatic urothelial carcinoma ineligible for cisplatin-based therapy. J Clin Oncol. 2018;36(15).

  31. • Powles T, Gschwend JE, Loriot Y, Bellmunt J, Geczi L, Vulsteke C, et al. Phase 3 KEYNOTE-361 trial: Pembrolizumab (pembro) with or without chemotherapy versus chemotherapy alone in advanced urothelial cancer. J Clin Oncol. 2017;35. Ongoing phase 3 trial of pembrolizumab in first-line cisplatin-eligible mUC.

  32. • Galsky MD, Grande E, Davis ID, Santis MD, Arija JAA, Kikuchi E, et al. IMvigor130: A randomized, phase III study evaluating first-line (1L) atezolizumab (atezo) as monotherapy and in combination with platinum-based chemotherapy (chemo) in patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC). J Clin Oncol. 2018;36(15_suppl):TPS4589-TPS Ongoing phase 3 trial of atezolizumab in first-line cisplatin-eligible mUC.

    Article  Google Scholar 

  33. Keytruda (pembrolizumab) or tecentriq (atezolizumab): FDA alerts health care professionals and investigators: FDA statement—decreased survival in some patients in clinical trials associated with monotherapy: U.S. Department of Health and Human Services; 2018 [Available from: https://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm608253.htm.

  34. Powles T, Grivas P, Aragon-Ching JB, Faroun Y, Kessler ER, Tomita Y, et al. A multicentre, international, randomised, open-label phase 3 trial of avelumab plus best supportive care (BSC) vs BSC alone as maintenance therapy after first-line platinum-based chemotherapy in patients with advanced urothelial cancer (JAVELIN bladder 100). Ann Oncol. 2016;27.

  35. Yafi FA, Aprikian AG, Chin JL, Fradet Y, Izawa J, Estey E, et al. Contemporary outcomes of 2287 patients with bladder cancer who were treated with radical cystectomy: a Canadian multicentre experience. BJU Int. 2011;108(4):539–45.

    Article  Google Scholar 

  36. Shabsigh A, Korets R, Vora KC, Brooks CM, Cronin AM, Savage C, et al. Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol. 2009;55(1):164–76.

    Article  Google Scholar 

  37. Bajorin D, Galsky MD, Gschwend JE, Tomita Y, Azrilevich A, Witjes F. A phase III, randomized, double-blind, multicenter study of adjuvant nivolumab vs placebo in patients (pts) with high-risk invasive urothelial carcinoma (UC; CheckMate 274). Ann Oncol. 2017;28.

  38. Powles T, Rodriguez-Vida A, Duran I, Crabb SJ, Van der Heijden MS, Pous AF. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS). J Clin Oncol. 2018;36(15).

  39. Hoimes CJ, Abouassaly R, Saltzman JN, Fleming MT, Hoffman-Censits JH, Byrd T, et al. HCRN GU14-188: neoadjuvant pembrolizumab (P) and gemcitabine (G) with or without cisplatin (C) in muscle invasive urothelial cancer (MIUC). Am Soc Clin Oncol; 2016.

  40. Gupta S, Agarwal N, Konety BR, Weight CJ, Thyagarajan B, Murugan PJ. Phase II trial of neoadjuvant nivolumab with cisplatin and gemcitabine in muscle-invasive bladder cancer patients undergoing radical cystectomy. J Clin Oncol. 2018;36(6).

  41. Gray PJ, Fedewa SA, Shipley WU, Efstathiou JA, Lin CC, Zietman AL, et al. Use of potentially curative therapies for muscle-invasive bladder cancer in the United States: results from the National Cancer Data Base. Eur Urol. 2013;63(5):823–9.

    Article  Google Scholar 

  42. Premo C, Apolo AB, Agarwal PK, Citrin DE. Trimodality Therapy in Bladder Cancer Who, What, and When? Urol Clin N Am. 2015;42(2):169−+.

    Article  Google Scholar 

  43. Joshi M, Tuanquin L, Kaag M, Zakharia Y, Liao J, Merrill S. Phase Ib study of concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with urothelial cancer of the bladder: BTCRC-GU15-023 study. J Clin Oncol. 2018;36(6).

  44. Herr HW, Milan TN, Dalbagni G. BCG-refractory vs. BCG-relapsing non muscle-invasive bladder cancer: a prospective cohort outcomes study. Urol Oncol-Semin Ori. 2015;33(3).

  45. Black PC, Catherine T, Lerner SP, McConkey DJ, Lucia MS, Woods M. S1605: Phase II trial of atezolizumab in BCG-unresponsive nonmuscle invasive bladder cancer. J Clin Oncol. 2018;36(6).

  46. Kamat AM, Bellmunt J, Choueiri TK, Nam K, De Santis M, Dreicer R, et al. KEYNOTE-057: Phase 2 study of pembrolizumab for patients (pts) with Bacillus Calmette Guerin (BCG) unresponsive, high-risk non-muscle-invasive bladder cancer (NMIBC). J Clin Oncol. 2016;34(15).

  47. Alanee SR, Robinson K, Sana S. Phase I trial of safety of combining BCG with pembrolizumab in patients with high grade superficial bladder cancer unresponsive to previous intravesical therapy. J Clin Oncol. 2018;36(5).

  48. Sharma P CM, Calvo E, Kim J. Efficacy and safety of nivolumab plus ipilimumab in previously treated metastatic urothelial carcinoma. Presented at the 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016)2016 [updated May, 2016. Available from: https://cdn.mednet.co.il/2017/01/Sharma.pdf.

  49. Galsky MD, Powles T, Li S, Hennicken D, Sonpavde G. A phase 3, open-label, randomized study of nivolumab plus ipilimumab or standard of care (SoC) vs SoC alone in patients (pts) with previously untreated unresectable or metastatic urothelial carcinoma (mUC; CheckMate 901). J Clin Oncol. 2018;36(15_suppl):TPS4588-TPS.

    Article  Google Scholar 

  50. Balar AV, Mahipal A, Grande E, Villalobos VM, Salas S, Kang TW, et al. Abstract CT112: Durvalumab + tremelimumab in patients with metastatic urothelial cancer. Cancer Res. 2018;78(13 Supplement):CT112-CT.

    Article  Google Scholar 

  51. Powles T, Galsky MD, Castellano D, Heijden MSVD, Petrylak DP, Armstrong J, et al. A phase 3 study of first-line durvalumab (MEDI4736) ± tremelimumab versus standard of care (SoC) chemotherapy (CT) in patients (pts) with unresectable stage IV urothelial bladder cancer (UBC): DANUBE. J Clin Oncol. 2016;34(15_suppl):TPS4574-TPS.

    Article  Google Scholar 

  52. Gao JJ, Siefker-Radtke AO, Navai N, Campbell MT, Slack R, Guo C. A pilot pre-surgical study evaluating anti-PD-L1 durvalumab (durva) plus anti-CTLA-4 tremelimumab (treme) in patients with muscle-Invasive, high-risk urothelial bladder carcinoma who are ineligible for cisplatin-based neoadjuvant chemotherapy. J Clin Oncol. 2018;36(15).

  53. Charych DH, Hoch U, Langowski JL, Lee SR, Addepalli MK, Kirk PB, et al. NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clin Cancer Res. 2016;22(3):680–90.

    Article  CAS  Google Scholar 

  54. Bernatchez C, Haymaker C, Tannir NM, Kluger H, Tetzlaff M, Bentebibel SE, et al. A CD122-biased agonist increases CD8+ T cells and natural killer cells in the tumor microenvironment; making cold tumors hot with NKTR-214. Cough. 2016;5(1):3.

    Google Scholar 

  55. Bernatchez C, Haymaker CL, Hurwitz ME, Kluger HM, Tetzlaff MT, Jackson N, et al. Effect of a novel IL-2 cytokine immune agonist (NKTR-214) on proliferating CD8+T cells and PD-1 expression on immune cells in the tumor microenvironment in patients with prior checkpoint therapy. J Clin Oncol. 2017;35:2545.

    Article  Google Scholar 

  56. Vaena DA, Chaves J, Vogelzang NJ, Matrana MR, Gabayan AE, Riese MJ. PROPEL: A phase 1/2 trial of NKTR-214 (CD122-biased agonist) combined with anti-PD-1 (pembrolizumab) or anti-PD-L1 (atezolizumab) in patients (pts) with advanced solid tumors. J Clin Oncol. 2018;36(15).

  57. Diab A, Hurwitz ME, Tannir N, Bernatchez C, Haymaker C, Bentebibel SE, et al. PIVOT-02: a phase 1/2, open-label, multicenter, dose escalation and dose expansion study of NKTR-214 and nivolumab in patients with select, locally advanced or metastatic solid tumor malignancies. Ann Oncol. 2017;28.

  58. Motz GT, Coukos G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat Rev Immunol. 2011;11(10):702–11.

    Article  CAS  Google Scholar 

  59. Petrylak DP, Arkenau H-T, Perez-Gracia JL, Krebs M, Santana-Davila R, Yang J, et al. A multicohort phase I study of ramucirumab (R) plus pembrolizumab (P): interim safety and clinical activity in patients with urothelial carcinoma. J Clin Oncol. 2017;35(6_suppl):349.

    Article  Google Scholar 

  60. Herbst RS, Chau I, Petrylak DP, Arkenau H-T, Bendell JC, Santana-Davila R, et al. Activity of ramucirumab (R) with pembrolizumab (P) by PD-L1 expression in advanced solid tumors: phase 1a/b study in later lines of therapy. J Clin Oncol. 2018;36(15_suppl):3059.

    Article  Google Scholar 

  61. Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7.

  62. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi YC, Yu PW, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298–308.

    Article  CAS  Google Scholar 

  63. Apolo AB, Mortazavi A, Stein MN, Davarpanah NN, Nadal RM, Parnes HL, et al. A phase I study of cabozantinib plus nivolumab (CaboNivo) and cabonivo plus ipilimumab (CaboNivoIpi) in patients (pts) with refractory metastatic (m) urothelial carcinoma (UC) and other genitourinary (GU) tumors. J Clin Oncol. 2017;35(15_suppl):4562.

    Article  Google Scholar 

  64. Maia MC, Agarwal N, McGregor BA, Vaishampayan UN, Choueiri TK, Green MC. Phase 1b trial of cabozantinib in combination with atezolizumab in patients with locally advanced or metastatic urothelial carcinoma (UC) or renal cell carcinoma (RCC). J Clin Oncol. 2018;36(5).

  65. Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013;14(6):552–62.

    Article  CAS  Google Scholar 

  66. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12(4):237–51.

    Article  CAS  Google Scholar 

  67. Powles T, Kilgour E, Mather R, Galer A, Arkenau HT, Farnsworth A, et al. BISCAY, a phase Ib, biomarker-directed multidrug umbrella study in patients with metastatic bladder cancer. J Clin Oncol. 2016;34(15).

  68. Gavine PR, Mooney L, Kilgour E, Thomas AP, Al-Kadhimi K, Beck S, et al. AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res. 2012;72(8):2045–56.

    Article  CAS  Google Scholar 

  69. Joerger M, Cassier P, Penel N, Cathomas R, Richly H, Schostak M. Rogaratinib treatment of patients with advanced urothelial carcinomas prescreened for tumor FGFR mRNA expression. J Clin Oncol. 2018;36(6).

  70. Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376(9737):245–51.

    Article  CAS  Google Scholar 

  71. Do K, Wilsker D, Ji JP, Zlott J, Freshwater T, Kinders RJ, et al. Phase I study of single-agent AZD1775 (MK-1775), a Wee1 kinase inhibitor, in patients with refractory solid tumors. J Clin Oncol. 2015;33(30):3409−+.

    Article  Google Scholar 

  72. Basu B, Dean E, Puglisi M, Greystoke A, Ong M, Burke W, et al. First-in-human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor AZD2014. Clin Cancer Res. 2015;21(15):3412–9.

    Article  CAS  Google Scholar 

  73. Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J, et al. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci Transl Med. 2015;7(314).

  74. Janne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013;14(1):38–47.

    Article  Google Scholar 

  75. Challita-Eid PM, Satpayev D, Yang P, An ZL, Morrison K, Shostak Y, et al. Enfortumab Vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res. 2016;76(10):3003–13.

    Article  CAS  Google Scholar 

  76. Petrylak DP, Perez RP, Zhang J, Smith DC, Ruether JD, Sridhar SS, et al. A phase I study of enfortumab vedotin (ASG-22CE; ASG-22ME): updated analysis of patients with metastatic urothelial cancer. J Clin Oncol. 2017;35:106.

    Article  Google Scholar 

  77. Rosenberg JE SS, Zhang J, Smith DC, Ruether JD, Flaig TW, Baranda JC, Lang JM, Plimack ER, Sangha RS, Heath EI editors. Updated results from the enfortumab vedotin phase 1 (EV-101) study in patients with metastatic urothelial cancer (mUC). ASCO Annual Meeting; 2018; Chicago, IL.

  78. Hoimes CJ, Petrylak DP, Flaig TW, Carret AS, Melhem-Bertrandt A, Rosenberg JE. EV-103 study: A phase 1b dose-escalation and doseexpansion study of enfortumab vedotin in combination with immune checkpoint inhibitor (CPI) therapy for treatment of patients with locally advanced or metastatic urothelial cancer. J Clin Oncol. 2018;36(6).

  79. Cortes J, O’Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914–23.

    Article  CAS  Google Scholar 

  80. Yan M, Schwaederle M, Arguello D, Millis SZ, Gatalica Z, Kurzrock R. HER2 expression status in diverse cancers: review of results from 37,992 patients. Cancer Metastasis Rev. 2015;34(1):157–64.

    Article  CAS  Google Scholar 

  81. Doi T, Shitara K, Naito Y, Shimomura A, Fujiwara Y, Yonemori K, et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol. 2017;18(11):1512–22.

    Article  CAS  Google Scholar 

  82. Andtbacka R, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33(25):2780–8.

    Article  CAS  Google Scholar 

  83. Chesney J, Puzanov I, Collichio F, Singh P, Milhem MM, Glaspy J, et al. Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. J Clin Oncol. 2018;36(17):1658–67.

    Article  CAS  Google Scholar 

  84. Pandha H, Harrington K, Ralph C, Melcher A, Gupta S, Akerley W, et al. Abstract CT115: phase 1b KEYNOTE 200 (STORM study): a study of an intravenously delivered oncolytic virus, Coxsackievirus A21 in combination with pembrolizumab in advanced cancer patients. AACR; 2017.

  85. Harb WA, Cerec V, McElwaine-Johnn H, Champion B, Alvis S, Jain N, et al. A phase I study of pembrolizumab in combination with enadenotucirev (EnAd) (SPICE) in subjects with metastatic or advanced carcinoma. J Clin Oncol. 2016;34(15).

  86. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22.

    Article  CAS  Google Scholar 

  87. Ott PA, Govindan R, Naing A, Friedlander TW, Margolin K, Lin JJ, et al. Abstract CT125: a personal neoantigen vaccine, NEO-PV-01, with anti-PD1 induces broad de novo anti-tumor immunity in patients with metastatic melanoma, NSCLC, and bladder cancer. AACR; 2018.

  88. Slingluff CL, Dasilva D, Schwarzenberger P, Ricciardi T, Ryan MJMA, Venhaus RR, et al. Phase 1/2 study of in situ vaccination with tremelimumab plus intravenous (IV) durvalumab plus poly-ICLC in patients with select relapsed, advanced cancers with measurable, biopsy-accessible tumors. J Clin Oncol. 2017;35:TPS3106.

    Article  Google Scholar 

  89. June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379(1):64–73.

    Article  CAS  Google Scholar 

  90. Srivastava S, Riddell SR. Chimeric antigen receptor T cell therapy: challenges to bench-to-bedside efficacy. J Immunol. 2018;200(2):459–68.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, NYU School of Medicine, New York, NY, USA

    Michael Lattanzi & Arjun V. Balar

  2. Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA

    Arjun V. Balar

  3. NYU School of Medicine, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, 160 East 34th Street, 10th Floor, New York, NY, 10016, USA

    Arjun V. Balar

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  1. Michael Lattanzi
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Correspondence to Arjun V. Balar.

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Conflict of Interest

Michael Lattanzi has no conflicts of interest.

Arjun V. Balar has received research funding from AstraZeneca/MedImmune, Genentech/Roche, Merck, and Seattle Genetics/Astellas and has received compensation from AstraZeneca/MedImmune, Genentech/Roche, Merck, Incyte, Seattle Genetics/Astellas, Cerulean Pharma, Pfizer/EMD Serono, and Eli Lilly for service as a consultant/advisor.

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This article is part of the Topical Collection on Genitourinary Cancers

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Lattanzi, M., Balar, A.V. Current Status and Future Direction of Immunotherapy in Urothelial Carcinoma. Curr Oncol Rep 21, 24 (2019). https://doi.org/10.1007/s11912-019-0775-5

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  • DOI: https://doi.org/10.1007/s11912-019-0775-5

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